Deposition of methyl marks on H3K4 (histone 3 lysine 4) and their significance during Caenorhabditis elegans embryogenesis

Abstract

Covalent modifications of the histone proteins can alter chromatin structure and have crucial effects on DNA-based processes. For example, methylation at lysine 4 on histone 3 (H3K4) is correlated with activation of transcription. H3K4 methylation is deposited by a variety of complexes called MLL/SET/COMPASS complexes, which have in common a core complex including WDR-5, RBBP-5 and ASH-2. It remains unclear whether the deposition of H3K4 methylation by the core complex is important for transcriptional regulation or just a consequence of transcription. In order to start investigating this question, we developed a system in which we could track the changes of H3K4 methylation at a cellular level by using the C. elegans embryonic and larval development system. In this system, we found that H3K4 methylation is lineage and stage specific. Importantly, H3K4me2/me3 are deposited according to transcription states (Chapter 3). In order to link this observation to the MLL/SET/COMPASS complexes, we investigated the contribution of each core component toward deposition of H3K4 methyl marks. We found that the contribution of each core component toward H3K4 methylation is different according to the methyl mark and developmental stage involved. Unexpectedly, we also revealed that RBBP-5 and ASH-2 can antagonise deposition of H3K4 methylation in the primordial germ cells (Chapter 4). We next characterised the phenotypic consequences of altering H3K4 methylation in embryos. Our results indicate that removal of the core components causes defects in C. elegans viability and lineage specification (Chapter 5). Importantly, we also uncovered the role of the MLL/SET/COMPASS complex on RNA Pol II processivity. In summary, this study shed light on the individual role of MLL/SET/COMPASS core components in the deposition of H3K4 methyl marks, and it revealed that H3K4 methylation has an impact on transcriptional regulation.

Date of Award	1 Aug 2015
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Gino Poulin (Supervisor) & Alan Whitmarsh (Supervisor)